T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in development of allograft rejection in an established MHC-II mismatched (bm12 into B6) model of chronic cardiac allograft rejection and vasculopathy (CAV). Intriguingly, and in contradistinction to IFN-?-/- mice that are protected from CAV, T-bet-/- recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17 producing CD4 T cells. Concurrently, T-bet-/- mice exhibit a Th1-deficient environment characterized by profound IFN-? deficiency, a Th2 switch characterized by increased production of IL-4, IL-5, IL-10, and IL-13 cytokines, and increased production of the proinflammatory cytokines IL-6, IL-12p40 and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection in T-bet-/- mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet-/- mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first report establishing that in the absence of Th1 mediated alloimmune responses, CD4 Th17 cells mediate a proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for development of novel therapies to target this intractable problem in clinical solid organ transplantation. Based on published and our preliminary data, T-bet by affecting T helper cell differentiation plays an important role in inhibiting a proinflammatory Th17 type immune response. Our central hypothesis is that Th17 immunity plays a critical role in mediating aggressive alloimmune responses, allograft rejection and resistance to tolerance induction, particularly in the absence of Th1 immunity. The main goal of this proposal is to define the functions and mechanisms of action of Th17 cells in mediating alloimmune responses in vivo and identifying targets for inhibition of Th17 immunity as a means of developing novel strategies to achieve durable and reproducible tolerance in murine transplant models to translate to non-human primates and ultimately to humans.